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Urology & Nephrology Open Access Journal

Research Article Volume 5 Issue 1

Association of High Altitude Hypertension with Angiotensin Converting Enzyme (ACE) Gene Insertion/Deletion Polymorphism

Shikha Chandel,1,2 Badarud Doza,1,3 Kumar Digvijay2

1Department of Human Genetics, Guru Nanak Dev University, India
2Department of Nephrology and Research, Sir Ganga Ram Hospital, India
3Aligarh Muslim university, off campus Murshidabad, India

Correspondence: Kumar Digvijay, Department of Human Genetics, Guru Nanak Dev University, Amritsar, Department of Nephrology and Research, Sir Ganga Ram Hospital, Delhi, India

Received: November 18, 2016 | Published: June 23, 2017

Citation: Chandel S, Doza B, Digvijay K (2017) Association of High Altitude Hypertension with Angiotensin Converting Enzyme (ACE) Gene Insertion/ Deletion Polymorphism. Urol Nephrol Open Access J 5(1): 00155. DOI: 10.15406/unoaj.2017.05.00155

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Abstract

The study included ACE gene I/D polymorphism and its association between high altitude hypertension. Genetic, biochemical, anthropometric and Physiometeric results were analyzed using statistical software. The results were non-significant for I/D polymorphism.

Objective: ACEis the major enzyme of hypertension and with most commonly reviewed I/D polymorphism. High-altitude exposes various physiological and biochemical changes, which contributes a rise in systemic blood pressure of the body. There are very few studies available in North-India, with a core focus on the high altitude hypertension. Therefore, a current study supported an interest to find out the association of high altitude hypertension with ACE gene I/D polymorphism.

Methods: to study the significant association with respect to altitude, genetic, biochemical, anthropometric and physio-metric comparison were conducted among 98 individuals where 489nbeing hypertensive patients and other half being normotensive, inclusive of both males and females. The entire results were finally examined and analyzed using statistical software SPSS 16.0 version.

Results: According to study results, mean arterial blood pressure and triglycerides were significantly (p<0.05) associated with SBP among both hypertensive and normotensives. Whereas HDL, LDL-HDL ratio, CHO-HDL were significantly associated only among hypertensive, and age, PP, and SpO2 have been significantly (p<0.05) associated with SBP among normotensive, a strong predictor for SBP.

Conclusion: The genotypic observations were visibly linked with the disease, however, the results were statistically non-significant (ID/DD vs. II; OR: 0.54, 95% CI: 0.20-1.44, p= 0.217). A further study with considerate knowledge of noteworthy dynamics, mainly, altitude, population size, and ethnicity are recommended.

Keywords: altitude, cholesterol, blood pressure, polymorphism, hypertension

Abbreviations

ACE, angiotensin converting enzyme; AT1R, angiotensin ii type 1 receptor; AT2R, angiotensin II type 2 receptor; BMI, body mass index; CHO, total cholesterol; CHO-HDL, total cholesterol-high density lipoproteins ratio; CI, confidence interval; D, deletion; DBP, diastolic blood pressure; HDL, high density lipoproteins; HWE, hardy weinberg equilibrium; I: insertion; I/D, insertion/deletion; LDL, low density lipoproteins; LDL-CHO, low density lipoproteins-total cholesterol ratio; MAP, mean arterial blood pressure; PP, pulse pressure; PR, pulse rate; OR, odds ratio; RAS, renin-angiotensin System; SBP, systolic blood pressure; TG: triglycerides; VLDL, very low density lipoproteins; WC, waist circumference; WHR, waist-to-hip ratio

Introduction

Human essential hypertension accounts for 90% of the hypertensive population, is a complex multifactorial and polygenic disorder1,2 affecting large groups with a genetic heritability ranging from 15% to 35%.3-6 The interplay between environmental and genetic factors is a major determinant of the final phenotype in hypertension.2 Several genes: angiotensinogen gene (AGT), angiotensin I-converting enzyme (ACE), angiotensin II type 1-receptor (AT1-R) and angiotensin II type 2- receptor (AT2-R) have been reported an association with hypertension.7-11 ACE is the major enzyme of the renin-angiotensin-aldosterone system (RAAS), functions conversion of angiotensin I to angiotensin II which binds to plasma membrane receptors, producing arteriolar constriction and a rise in systolic and diastolic blood pressure. ACE is encoded by a 21 kb gene with 26 exons, located on chromosome 17. A polymorphism of ACE gene involves the insertion (I) and deletion (D) of 287 bp Alu repeat sequence near the 3’ end of the intron. Physiologically it has been reported ACE I/D accounts for 50% of the inter-individual variability of plasma ACE concentration.12-14

High-altitude environments imply stress factors: hypoxia, cold, humidity, solar radiation, cosmic radiation and isolation, causing many physiological and biochemical changes in body, including structural changes in the walls of small pulmonary arteries, predominantly increased masculinization, increased pulmonary vascular resistance and sustained elevation of pulmonary arterial pressure, instigating high altitude pulmonary hypertension (HAPH).15-18 In humans, large inter-individual differences exist in the magnitude of the pulmonary pressure response to hypoxia,19-22 with some subjects demonstrating exaggerated increases in pulmonary arterial pressure.23,24 There are very few studies available in North-India where the high altitude hypertension has been focused. Therefore, the objective of this study was designed, supporting an interest to find out the association of high altitude hypertension with ACE gene I/D polymorphism.

Methods

Study protocol

This study was a prospective observation of genetic and biochemical analysis among hypertensive patients and normotensive controls, to analyze the significant association of hypertension in concordance to altitude. The study protocol was approved by the institutional board of committee and experiments were performed in the registered department of Human Genetics, Guru Nanak Dev University, and Amritsar, India.

Sample collection

A total of 98 individual samples, 49 hypertensive and 49 normotensives, both males and females included, were collected from high altitude areas of Himachal Pradesh and low altitude areas of Punjab. The patient samples were collected from clinics and hospitals and control samples were taken via door to door study. The patient and control data was collected on a pre-designed Performa, referring to demographic and clinical features. A 3-5 ml of peripheral blood from each individual was withdrawn with a sterile disposable syringe, after having the informed consent. Blood and plasma samples were stored differently for genetic and biochemical analysis. Also, the body Physiometeric measurements of individuals were noted, as useful annotations during statistical analysis of overall data.

Genetic studies

To study ACE I/D Polymorphism, DNA isolation using phenol-chloroform method was performed using the blood samples of individuals from both hypertensive and normotensive groups. After confirming the quality of DNA (min. 50ng/µl) using Agarose gel electrophoresis (ƛ200) and NanoDrop1000 techniques, proceeded the next step of PCR reactions, an enzymatic amplification of DNA fragments (95⁰C- 5 min. and 30 sec denaturation, 56⁰C- 30 sec. annealing, 72⁰C- 30 sec. and 5 min. extension, for 30 cycles), using ACE I/D gene specific primers (F- 5’-CTG GAG ACC ACT CCC ATC CTT TCT -3’, R- 5’-GAT GTG GCC ATC ACA TTC GTC AGA TTT-3’). The amplicons were analyzed for I/D (I at 490bp and D at 190bp) of the 287bp Alu repeats in an ACE gene on 1.5% agarose gel, stained with Ethidium Bromide, using the 100pb DNA marker to study the genotyping pattern of both the groups (Figure 1).

Figure 1 Gel Picture showing I/D polymorphism of ACE gene.
Lane 1: 100 bp DNA ladder
Lane 2-6: Random samples
Lane 7: Positive control
Lane 8: Negative control

Biochemical studies

Total cholesterol (CHO) (desirable <200, borderline 200-239, high >240), triglycerides (desirable <150, borderline 150-199, high 200-500), high density lipopolysaccharides (HDL) (low > 40, high < 50), low-density lipopolysaccharides (LDL) and very low-density lipopolysaccharides (VLDL), HDL-LDL ratios, CHO-LDL ratio were calculated via kit based techniques, using blood plasma separated from the collected blood samples of both groups.

Anthropometric and physiometeric measurements

The height, weight, waist and hip circumference calculated for each individual using standard anthropometric technique and the physio metric variables: systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse rate, taken 2 hours after meal, using the calculated average of 3-4 time measurements via automatic machine, saturated oxygen pressure (SpO2) using pulse oxy-meter, were calculated for both groups.

Statistics

The data collected from genetic, biochemical, anthropometric and Physiometeric studies were analyzed statistically using SPSS (16.0 version), to evaluate the associated significance in this study. All 98 individuals included, were the only eligible candidates supporting WHO (2009) criteria of normal and hypertensive blood pressure measurements in the conducted study. The analysis included, differential statistical comparisons (for Physiometeric, anthropometric and biochemical variables), linear and multivariate regression (to calculate significant predictors of SBP and DBP), risk estimation (odds ratio, CI-95%, for SBP and DBP), allelic frequency distribution (with respect to ACE genotypes inclusive of risk factors (odds ratio, CI- 95%), Figure 2), for the individuals of both groups. All statistical tests were two-sided with a significance level of 0.05.

Figure 2  Genotypic and allelic frequencies distributions in high altitude hypertensive individuals and low altitude normotensive individuals.

Results

In this study, we compared descriptive statistics for different anthropometric, psychometric, biochemical and lifestyle variables with a p-value (p<0.05) of significance among hypertensive and normotensive individuals (Table 1). The study revealed, mean values of age, SBP, DBP, MAP, PP, SpO2, CHO, LDLs and VLDLs were significantly higher (p<0.05) for all the variables, except SpO2, with significant lower p-value among high altitude hypertensive individuals.

Variable

Hypertensive

Normotensive

t

p-Value

N

Mean

SD

N

Mean

SD

Age(years)

49

55.02

13.52

49

49.87

9.67

2.088

<0.042

Height(cm)

49

1.62

0.085

49

1.64

0.09

0.894

0.376

Weight(kg)

49

71.09

12.26

49

69.56

10.52

0.730

0.469

Body mass index(BMI)(kg/m2)

49

26.96

4.27

49

25.93

3.54

1.375

0.176

Waist circumference(cm)

49

96.44

9.96

49

93.26

10.75

1.568

0.124

Hip circumference(cm)

49

99.43

8.38

49

99.16

7.97

0.166

0.869

Waist-hip ratio

49

0.97

0.06

49

0.94

0.08

1.861

0.69

Systolic blood pressure(mmHg)

49

146.55

17.64

49

130.12

13.22

5.097

<0.000

Diastolic blood pressure(mmHg)

49

90.32

10.06

49

79.97

9.09

5.327

<0.000

MAP(mmHg)

49

109.07

11.57

49

96.69

9.80

5.557

<0.000

Pulse Pressure(mmHg)

49

56.22

12.96

49

50.14

8.84

2.839

<0.007

Pulse rate(counts/min)

49

77.65

14.47

49

78.16

9.83

0.185

0.854

SpO2 (%)

49

97.20

1.92

49

97.91

0.73

2.449

<0.018

Alcohol

49

1.61

0.88

49

1.43

0.67

1.176

0.245

Smoking

49

1.48

0.86

48

1.25

0.56

1.631

0.110

Exercise

49

0.73

0.49

48

0.58

0.57

1.533

0.132

Food habit

49

1.48

0.50

49

1.38

0.49

1.000

0.322

Physical fitness

49

1.89

0.30

49

1.93

0.31

0.629

0.533

Total-cholesterol (CHO)(mg/dl)

41

207.02

88.40

49

153.46

50.39

2.933

<0.006

Triglycerides(mg/dl)

41

199.26

129.38

49

193.59

103.54

0.017

0.987

High density lipoproteins(mg/dl)

41

50.56

28.81

49

45.22

32.45

0.742

0.463

Low density lipoprotein(mg/dl)

41

116.59

94.89

49

69.52

48.64

2.528

<0.016

Very low density lipoprotein

41

39.85

25.87

49

38.71

20.70

3.464

<0.001

LDL-HDL ratio

41

3.00

2.69

49

2.03

1.69

1.616

0.114

CHO-LDL ratio

41

5.01

2.72

49

4.15

2.25

1.192

0.240

Table 1 Descriptive statistics for different studied variables among Hypertensive and Normotensive groups
HDL, high density lipoprotein, LDL, low density lipoproteins

Regression models

The descriptive results were further continued by calculating significant predictors of SBP and DBP through univariate regression analysis. We found during analysis that DBP, MAP, and PP are significantly associated (p<0.05) with SBP among both groups whereas height and weight are significantly associated (p<0.05) with SBP among normotensive individuals. It was also found during analysis that MAP and triglycerides were significantly associated (p<0.05) with SBP among hypertensive and normotensive individuals. HDL, LDL-HDL ratio, and CHO-HDL ratios were significantly associated among hypertensive only and on the other hand age, pulse pressure, and SpO2 were significantly associated (p<0.05) with SBP among low altitude normotensive and therefore strong predictor for SBP (Table 2). Table 3 describes, LDL-HDL ratio and CHO-HDL are significantly associated (p<0.05) among hypertensive individuals whereas age, mean arterial pressure and pulse pressure were found significantly associated (p<0.05) among normotensive individuals with DBP.

Variables

High Altitude Hypertensive

Low Altitude Normotensive

Coefficient

Std. Error

t

p-Value

Coefficient

Std. Error

t

p-Value

Age(years)

0.370

0.224

1.655

0.105

0.400

0.189

2.12

<0.040

Height(cm)

-1123.1

806.08

1.393

0.170

160.92

105.83

1.52

0.136

Weight(kg)

0.406

0.366

1.107

0.274

-1.13

1.275

0.893

0.377

Body mass index(BMI)(kg/m2)

-0.384

1.258

0.305

0.762

4.498

3.401

1.323

0.193

Waist circumference(WC)(cm)

0.729

0.528

1.380

0.174

-0.364

0.257

1.418

0.163

Hip circumference(cm)

0.001

0.001

1.288

0.204

-0.001

0.005

0.215

1.053

Waist-hip ratio

0.008

0.0198

0.437

0.664

0.045

0.005

0.903

0.371

Mean arterial pressure(mmHg)

3.00

0.02

10.3

<0.001

1.000

0.004

22.43

<0.001

Pulse pressure(mmHg)

1.149

0.117

9.804

1.043

0.667

0.004

13.24

<0.001

Pulse rate(counts/min)

0.117

0.011

1.033

0.307

0.134

0.188

0.711

0.481

SaO2 (%)

0.602

0.859

0.700

0.487

-5.76

2.486

2.321

<0.025

Total cholesterol(CHO)(mg/dl)

0.002

0.030

0.095

0.924

-0.014

0.042

0.340

0.735

Triglycerides(mg/dl)

0.040

0.020

1.984

<0.050

0.033

0.019

1.848

<0.05

HDL(mg/dl)

-0.182

0.092

1.958

<0.050

-0.095

0.063

0.015

0.988

LDL(mg/dl)

0.0405

0.053

0.763

0.450

-0.034

0.060

0.578

0.566

VLDL(mg/dl)

-0.09

0.157

0.595

0.556

0.191

0.141

1.350

0.184

LDL-HDL ratio

-14.08

6.127

2.299

<0.027

1.864

4.428

0.421

0.676

CHO-HDL ratio

12.9

4.978

2.593

<0.014

-0.827

2.942

0.281

0.780

Table 2 Calculation of significant predictor of systolic blood pressure (SBP) through multivariate regression analysis among high altitude hypertensive and low altitude low altitude normotensive individuals
HDL, high-density lipoproteins; LDL, low-density lipoproteins; VLDL, very low-density lipoproteins; R2: percent of variance

 

High Altitude Hypertensive

Low Altitude Normotensive

Variables

Coefficient

Std. Error

T

p-Value

Coefficient

Std. Error

t

p-Value

Age(years)

0.093

0.144

0.647

0.522

0.009

0.004

2.094

<0.042

Height(cm)

39.60

20.95

0.078

0.938

27.18

14.16

1.919

0.062

Weight(kg)

0.017

0.222

0.807

0.424

0.349

0.188

1.853

0.071

Body mass index(BMI)(kg/m2)

0.059

0.812

0.073

0.942

-0.80

0.576

1.399

0.169

Waist circumference(WC)(cm)

3.43

2.218

1.547

0.129

-0.28

1.918

0.148

0.883

Hip circumference(cm)

-3.37

2.009

1.679

0.100

0.459

1.730

0.265

0.792

Waist-hip ratio

-31.4

20.60

1.413

0.165

14.52

18.742

0.076

0.939

Mean arterial pressure(mmHg)

31.6

25.01

1024

0.625

1.00

0.0043

23.89

<0.001

Pulse pressure(mmHg)

0.149

0.117

1.274

0.209

-0.33

0.0051

6.139

<0.001

Pulse rate(counts/min)

0.117

0.113

1.033

0.307

0.002

0.0040

0.707

0.483

SaO2 (%)

0.602

0.859

0.700

0.487

0.002

0.0057

0.452

0.654

Total cholesterol(CHO)(mg/dl)

0.05

0.019

0.306

0.761

-0.04

0.0280

1.580

0.121

Triglycerides(mg/dl)

0.22

0.012

1.758

0.087

0.021

0.0127

1.717

0.093

HDL(mg/dl)

-0.05

0.058

0.897

0.375

-0.042

0.0421

1.018

0.314

LDL(mg/dl)

0.07

0.018

0.391

0.698

-0.025

0.0413

0.618

0.540

VLDL(mg/dl)

0.115

0.069

1.668

0.104

-0.024

0.0982

0.250

0.804

LDL-HDL ratio

-4.00

2.041

1.959

<0.05

-0.913

2.987

0.030

0.761

CHO-HDL ratio

4.422

2.013

2.197

<0.035

1.343

1.985

0.677

0.502

Table 3  Calculation of significant predictor of diastolic blood pressure (DBP) through multivariate regression analysis among hypertensive and normotensive individuals
HDL, high-density lipoproteins; LDL, low-density lipoproteins; VLDL, very low-density lipoproteins; R2, percent of variance

ACEallele and genotype with different genetic inheritance models between high altitude hypertensive cases and low altitude normotensive controls was shown in Table 4. The genotype and allele distributions of the ACE gene are almost similar and did not differ significantly between control and cases. No deviation from HWE has been found within both case and control group separately. However, there was a suggestive evidence of an association in a recessive model (OR: 0.83, 95% CI: 0.33-2.05, p= 0.681). It was also evident from the study that dominant model of inheritance has some protective impact with respect to high altitude hypertension but, the result found were not statistically significant (OR: 0.54, 95% CI: 0.20-1.44, p= 0.217) (Table s1 $ s2).

Total N (control + case)=88

 

Study

Genotype (%)

Allele (%)

p-Value

Dominant Model
(II/DD vs. II)

Co-Dominant Model
(DD vs. ID)= (ID vs. II)

Recessive Model
(DD vs. II/ ID)

Test for H.W.
Equilibrium

II

ID

DD

I

D

Genotype

Allele

OR
(95%CI)

p-Value

OR
(95% CI)

p-Value

OR
(95% CI)

p-value

x2

P

Control
(n=46)

15
(32)

22
(45)

9
(20)

54
(56)

40
(44)

0.46

0.306

0.54
(0.20-1.44)

0.217

0.76
(0.43-1.33)

0.331

0.83
(0.33-2.05)

0.681

0.033

0.855

Case
(n=42)

12
(29)

17
(40)

13
(31)

41
(49)

43
(51)

1.516

0.218

Table 4 Distribution of frequencies of Angiotensin Converting Enzyme (ACE) genotypes, alleles and genetic models in High Altitude Hypertensive Cases and Low Altitude normotensive Controls. Data are a number of subjects with each genotype and allele (frequency in percentage). OR- Odds Ratio, CI- Confidence Interval. ORs for different modes of inheritance have been calculated

Discussion

The study described the association between the ACE variant of high altitude hypertension in North Indian population. Many studies have shown a significant ACE gene D allele with essential hypertension.25-31 On the other hand, several researchers have shown no significant differences in the allele and genotype distribution of ACE gene polymorphism between low altitude normotensive control and high altitude hypertensive cases.32-39 The increase in body size has seen to be positively associated with blood pressure. There is a hypothesis that high body weight individuals are more likely to develop systemic hypertension at high altitude. On exposure to high altitude, systemic hypertension results from sympathetic stimulation and it may continue for many weeks. The involvement of the renin-angiotensin-aldosterone system (RAAS) in the control of the salt and water balance and thereby blood pressure is well known during hypoxia and high altitude exposure.35,36 At high altitude renal secretion is stimulated by decreased renal blood flow,37 which in turn activates the RAAS.16

In the present study, significant differences were observed in hypertension parameters such as pulse pressure, total cholesterol, low-density lipoproteins and very low-density lipoproteins. The mean values of all these parameters have been observed higher in high altitude hypertensive individuals, however, the content of O2 saturation (SpO2) has been higher in low-altitude individuals. In the present study of a small data set, the overall frequencies of the risk allele (D) have been higher in high altitude hypertensive individuals but, not significant (p =0.47) as compared to low altitude normotensive individuals. Therefore, D allele association hypothesis of hypertension in high altitude have not reflected to be true in the present study. The same also is true for I allele. The different covariates of hypertension such as body mass index, waist-hip ratio, waist circumference, hip circumference etc. have also not seen significantly different between high altitude hypertensive individuals. This observation also strengthens the present genotypic association analysis which did not show any association between ACE gene polymorphism in hypertension in high altitude cases.

In some population, the I allele may be in linkage disequilibrium with a mutation elsewhere in the gene, whereas in other population the D allele might be in linkage disequilibrium with the different ACE mutation. This might explain the association of essential hypertension and ACE-I allele. The recently described variety of potentially functionally variants in the ACE gene may support the alternative hypothesis.38-40 However, studies in North Indian Punjabi41-45 reported that diseases such as central obesity, type-2 Diabetes Miletus, and hyperlipidemia are more common but they have a low risk of developing cardiovascular diseases due to their strong genetic background. The low frequency of ACE DD genotype in this population might provide a protective effect for cardiovascular diseases. However, in this regard, not many data are available to support the present findings of this population.46

Conclusion

The present analysis suggests that this ACE gene polymorphism has no major influence on the susceptibility to elevate blood pressure phenotype with respect to high altitude. In the meantime, it should be noted that the present study has been carried out on a small sample size; despite this fact the findings which have been in homogenous population base study cannot be ignored.

Limitations

The study was carried as the thesis work of a Master’s student, therefore limited the number of subjects to be enrolled due to the short duration of time. Although the places were chosen were new for the study but the altitude was not really that higher to prove a significant association even in the lesser number of samples. It might have been more convincing with a better knowledge of population statistics and a larger group of cases enrolled. Though the results in conducted study could not give expected statistics but the non-statistical genotypic frequency results observed has given a supportive overview of ACE gene association with High altitude hypertension. If the study is conducted further with a larger data groups the results might be as promising as expected.

Acknowledgments

We gratefully acknowledge the study investigators, fellow researchers, clinicians, and patients and individuals who volunteered to participate in the study. The supported funding and work were done in the department of Human Genetics, Guru Nanak Dev University, and Amritsar, India. The work was re-analyzed by S.C and edited by K.D at institute of renal sciences and research, Sir Ganga Ram Hospital. Delhi, India.

Conflicts of interest

None.

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